ABSTRACT
Background: Despite its widespread use and favored profile, there are extensive variations in the treatment outcome of metformin therapy. Furthermore, studies reported that the inter-individual variability in the occurrence of metformin treatment associated side effects were related to the differences in individual genetic profiles. Thus, this study aimed to evaluate whether the reduced function methionine deletion at codon 420 (Met420del) variant of SLC22A1 (rs72552763) is associated with metformin induced gastrointestinal intolerance in Ethiopian patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A retrospective observational study was conducted on 47 T2DM patients on metformin treatment for <3 years to assess the association of SLC22A1 (rs72552763) polymorphism with metformin induced gastrointestinal intolerance. Accordingly, 24 metformin tolerant and 23 metformin intolerant individuals with T2DM were recruited. Genotyping of rs72552763 was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association to metformin induced gastrointestinal intolerance was assessed based on switching to a new class of glucose lowering agents or failure to up titrate dose due to metformin induced gastrointestinal intolerance. Chi-square, logistic regression and Mann-Whitney statistical tests were used as appropriate. Statistical significance was set at p < 0.05. Results: In our study, no significant association was observed between rs72552763 and metformin induced gastrointestinal intolerance. We found that the female gender and physical inactivity were risk factors for metformin gastrointestinal intolerance. Conclusion: Our study found that the Met420del variant of SLC22A1 (rs72552763) was not associated with metformin induced gastrointestinal intolerance in Ethiopian patients with T2DM. This is the study first to investigate the association of rs72552763 with metformin intolerance in the Ethiopian population with T2DM. However, the findings need to be cautiously interpreted given the relatively small sample size. In addition, a more complete investigation of SLC22A1 variants would be required to fully assess the effect of the gene on metformin induced gastrointestinal intolerance as several variants with a more severe loss of function have been described.
ABSTRACT
Objective: This study aimed to evaluate whether the M420del variants of SLC22A1 (rs72552763) is associated with metformin treatment response in Ethiopian patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A prospective observational cohort study was conducted on 86 patients with T2DM who had been receiving metformin monotherapy for <1 year. Patients showing ≥0.5% reduction in HbA1c levels from baseline within 3 months and remained low for at least another 3 months were defined as responders while those patients with <0.5% reduction in HbA1c levels and/or those whom started a new class of glucose-lowering drug(s) because of unsatisfactory reduction were defined as non-responders. In addition, good glycemic control was observed when HbA1c ≤7.0%, and the above values were regarded as poor. Genotyping of rs72552763 SNP was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association with metformin response and glycemic control were assessed by measuring the change in HbA1c and fasting blood glucose levels using Chi-square, logistic regression and Mann-Whitney U-test. Statistical significance was set at p <0.05. Results: The minor allele frequency of the rs72552763 SNP of SLC22A1 was 9.3%. Metformin response was significantly higher in deletion_GAT (del_G) genotypes as compared to the wild-type GAT_GAT (G_G) genotypes. Furthermore, a significantly lower median treatment HbA1 level was found in del_G genotypes as compared to G_G genotypes. However, the association of rs72552763 with metformin response was not replicated at the allele level. In contrast, the minor del_allele was significantly associated with good glycemic control compared to the G_allele, though not replicated at del_G genotypes level. Conclusion: This study demonstrated that metformin response was significantly higher in study participants with a heterozygous carrier of M420del variants of SLC22A1 as compared to the wild-type G_G genotypes after 3 months of treatment.
ABSTRACT
Genomic imprinting is an epigenetic phenomenon that leads to genes monoallelically expressed in a parent-of-origin-specific manner and plays an important role in the embryonic development and postnatal growth of mammals. Imprinted genes usually occur in clusters in a chromosomal region and are regulated by a cis-acting imprinting control region that involves differential DNA methylation modification. Igf2r, Slc22a2 and Slc22a3 are three maternally expressed genes on mouse chromosome 17. The paternally expressed long noncoding RNA (lncRNA) Air and the nonimprinted gene Slc22a1 are also located in the imprinted region. Comparative characterization of imprinted clusters between species is useful for us to understand the biological significance and epigenetic regulating mechanism of genomic imprinting. The aim of this study was to analyze the allelic expression pattern of AIR and SLC22A1-3 genes in cattle and to determine the role of DNA methylation in regulating gene expression. Allelic expression analysis was performed in bovine adult tissues and term placenta using an SNP-based approach. We found that IGF2R, AIR and SLC22A3 were monoallelically expressed in all detected bovine somatic tissues, including heart, liver, spleen, lung, kidney, muscle, fat and brain. In bovine placenta, IGF2R and SLC22A3 are maternally expressed; however, the AIR gene is paternally expressed. Tissue-specific monoallelic expression of SLC22A2 is detected in bovines, with monoallelic expression in the spleen and brain but biallelic expression in kidney tissues. SLC22A1 is only detected in bovine liver and kidney tissues and is biallelicly expressed, which is consistent with the imprint expression in mice. To determine the possible role of DNA methylation in regulating the monoallelic/imprinted expression of bovine IGF2R, AIR, SLC22A2, and SLC22A3 genes, we analyzed the DNA methylation status of CpG islands in the first exon of SLC22A2, the promoter region of SLC22A3 and region 2 in the second intron of the IGF2R gene by bisulfite sequencing. Two differentially methylated regions (DMRs) were detected in the first exon of bovine SLC22A3 and the common regions of IGF2R and AIR. This suggests that DNA methylation is involved in the regulation of monoallelic/imprinted expression of IGF2R, AIR and SLC22A3 genes in cattle.
Subject(s)
Genomic Imprinting , Organic Cation Transport Proteins/genetics , RNA, Long Noncoding , Receptor, IGF Type 2/genetics , Alleles , Animals , Cattle/genetics , DNA Methylation , Female , Mice , Placenta , PregnancyABSTRACT
Dyslipidemia is the main risk factor for coronary artery disease and is characterized by alterations in concentrations of lipids, including low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triacylglycerols. The participation of several genes in the development of dyslipidemia has been evidenced. Genetic variants in SLC22A1 have been associated with elevated cholesterol and LDL-c levels. The aim of this study was to evaluate the association between single-nucleotide polymorphisms (SNPs) in the SLC22A1 gene with atherogenic risk lipid levels in Mexican women. Anthropometric and biochemical measurements were performed, and four SNPs in SLC22A1 were genotyped by real-time polymerase chain reaction. The Hardy-Weinberg equilibrium was verified, and haplotype frequencies were calculated. We found significant differences between the allele frequencies of the SNPs analyzed with those reported in Mexico and in the world, which could be due to differences in the historical admixture of the women studied. Generalized linear models were evaluated to determine the association between genotypes and haplotypes with lipids levels. We identified a significant increase in total cholesterol and LDL-c levels in women who were carriers of the GA and AG genotypes of the polymorphisms rs628031 and rs594709, respectively, significant effect that is also shown in a dominant inheritance model. Interestingly, we identified an important relationship of the AGC-GAT haplotype with the elevation in LDL-c levels and AGA-GAT haplotype with the elevation in HDL-c levels. On the other hand, we found a strong linkage disequilibrium between the polymorphisms studied. Our results show that variants in the SLC22A1 gene influence serum levels of atherogenic risk lipids, suggesting that these variants probably affect the function of organic cation transporter-1 and therefore, on the regulation of lipid metabolism.
Subject(s)
Atherosclerosis , Catecholamine Plasma Membrane Transport Proteins/genetics , Dyslipidemias , Cholesterol, HDL , Cholesterol, LDL , Dyslipidemias/genetics , Female , Gene Frequency , Genotype , Haplotypes , Humans , Mexico , Polymorphism, Single NucleotideABSTRACT
AIM: To investigate the relationship between genotypes of rs628031, rs650284, rs683369 of SLC22A1 gene and the toxicities and clinical response of oxaliplatin in patients with colorectal cancer. METHODS: A total of 72 patients diagnosed as colorectal cancer during January 2018 to June 2018 were selected and all patients received oxaliplatin treatment. Their peripheral venous blood was collected and genotyping was conducted by using SNaPshot. The toxicities including gastrointestinal toxicity, hematological toxicity and peripheral neurotoxicity were evaluated according to the Common Terminology Criteria Adverse Events (CTCAE) Version 5.0. Clinical response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1). RESULTS: The results of Chi-test showed that different genotypes of SLC22A1 SNP sites rs628031 and rs683369 may be related to the toxicities and clinical response of oxaliplatin significantly. Specifically, when compared with the patients with GG type of rs628031, the patients with the GA or AA type had a lower incidence of grade 3 nausea and vomiting (P=0.017) and may also be less responsive to efficacy (P=0.008). When compared with the patients with CC type of rs683369, the patients with the GC or GG type had a lower incidence of grade 3 nausea and vomiting (P=0.002) and may also be less responsive to efficacy (P=0.014).CONCLUSION: The polymorphisms of SLC22A1 gene are closely related to the toxicities and clinical response of oxaliplatin in patients with colorectal cancer, which may be helpful for improving clinical treatment.
ABSTRACT
La diabetes mellitus tipo II (DM II) es una enfermedad que afecta una gran cantidad de individuos. Un medicamento empleado en el tratamiento de los pacientes es la metformina. Este medicamento es transportado al interior de los hepatocitos por un transportador codificado por el gen SLC22A1. Variantes en el gen con actividad reducida pueden disminuir la cantidad de metformina disponible en el hígado y reducir la respuesta terapéutica. Se propuso evaluar diferentes parámetros bioquímicos en relación a la dosis de metformina y la presencia de variantes en el transportador. Se estudiaron 103 pacientes mayores de 18 años con diagnóstico de DM II, tratados con 1700 mg/día de metformina por más de 6 meses. Se analizaron 5 polimorfismos en el gen SLC22A1, glucemia, HbA1c, función hepática, perfil lipídico y renal. Los niveles de HbA1c y de glucemia fueron más elevados en los pacientes que presentaban los polimorfismos R61C, G401S, M420del y G465R aunque la diferencia fue estadísticamente significativa sólo para la HbA1c en los pacientes que presentaban las variantes M420del y G465R (p=0,0273 y 0,0018, respectivamente). La presencia de polimorfismos con actividad reducida en el gen SLC22A1 afecta los niveles de glucemia y de HbA1c en pacientes con DM II cuando son tratados con metformina.
Diabetes mellitus type II (DM II) is a disease that affects a large number of individuals. One of the drugs used for the treatment is metformin. Metformin is delivered into hepatocytes by a transporter encoded by the SLC22A1 gene. Gene variants with reduced activity may decrease the amount of metformin available in the liver and reduce the therapeutic response. Various biochemical parameters were evaluated in relation to the metformin dose and the presence of transporter variants. A total of 103 patients older than 18 diagnosed with DM II who were treated with 1700 mg/day of metformin for more than six months were studied. Five polymorphisms in the SLC22A1 gene were analyzed as well as glycemia, HbA1c level, liver function, and lipid and kidney profiles. HbA1c and glycemia levels were higher in patients with the R61C, G401S, M420del and G465R polymorphisms; although the difference was statistically significant only for HbA1c in patients with the M420del and G465R variants (p=0.0273 and 0.0018, respectively). Polymorphisms with reduced activity in the SLC22A1 gene affect blood glucose levels and HbA1c in patients with DM II when they are treated with metformin.
O diabetes mellitus tipo II (DM II) é uma doença que afeta uma grande quantidade de indivíduos. Um medicamento utilizado no tratamento dos doentes é a metformina. Esse medicamento é transportado no interior dos hepatócitos por um transportador codificado pelo gene SLC22A1. Variantes no gene com atividade reduzida podem diminuir a quantidade de Metformina disponível no fígado e reduzir a resposta terapêutica. Propôs-se avaliar diferentes parâmetros bioquímicos em relação à dose da metformina e à presença de variantes no transportador. Foram estudados 103 pacientes maiores de 18 anos com diagnóstico de DM II tratados com 1700 mg/dia de metformina por mais de 6 meses. Foram analisados 5 polimorfismos no gene SLC22A1; glicemia, HbA1c, função hepática, perfil lipídico e renal. Os níveis de HbA1c e de glicemia foram superiores em doentes que apresentavam os polimorfismos R61C, G401S, M420del e G465R; embora a diferença seja estatisticamente significativa apenas para o HbA1c nos doentes que apresentavam as variantes M420del e G465R (p=0,0273 e 0,0018; respectivamente). A presença de polimorfismos com atividade reduzida no gene SLC22A1 afeta os níveis da glicemia e do HbA1c em doentes com DM II quando são tratados com metformina.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Diabetes Mellitus, Type 2/drug therapy , Metformin/standards , Organic Cation Transporter 1/blood , Blood Glucose , Diabetes Mellitus, Type 2 , Metformin/administration & dosage , Polymorphism, GeneticABSTRACT
La diabetes mellitus tipo II (DM II) es una enfermedad que afecta una gran cantidad de individuos. Un medicamento empleado en el tratamiento de los pacientes es la metformina. Este medicamento es transportado al interior de los hepatocitos por un transportador codificado por el gen SLC22A1. Variantes en el gen con actividad reducida pueden disminuir la cantidad de metformina disponible en el hígado y reducir la respuesta terapéutica. Se propuso evaluar diferentes parámetros bioquímicos en relación a la dosis de metformina y la presencia de variantes en el transportador. Se estudiaron 103 pacientes mayores de 18 años con diagnóstico de DM II, tratados con 1700 mg/día de metformina por más de 6 meses. Se analizaron 5 polimorfismos en el gen SLC22A1, glucemia, HbA1c, función hepática, perfil lipídico y renal. Los niveles de HbA1c y de glucemia fueron más elevados en los pacientes que presentaban los polimorfismos R61C, G401S, M420del y G465R aunque la diferencia fue estadísticamente significativa sólo para la HbA1c en los pacientes que presentaban las variantes M420del y G465R (p=0,0273 y 0,0018, respectivamente). La presencia de polimorfismos con actividad reducida en el gen SLC22A1 afecta los niveles de glucemia y de HbA1c en pacientes con DM II cuando son tratados con metformina.(AU)
Diabetes mellitus type II (DM II) is a disease that affects a large number of individuals. One of the drugs used for the treatment is metformin. Metformin is delivered into hepatocytes by a transporter encoded by the SLC22A1 gene. Gene variants with reduced activity may decrease the amount of metformin available in the liver and reduce the therapeutic response. Various biochemical parameters were evaluated in relation to the metformin dose and the presence of transporter variants. A total of 103 patients older than 18 diagnosed with DM II who were treated with 1700 mg/day of metformin for more than six months were studied. Five polymorphisms in the SLC22A1 gene were analyzed as well as glycemia, HbA1c level, liver function, and lipid and kidney profiles. HbA1c and glycemia levels were higher in patients with the R61C, G401S, M420del and G465R polymorphisms; although the difference was statistically significant only for HbA1c in patients with the M420del and G465R variants (p=0.0273 and 0.0018, respectively). Polymorphisms with reduced activity in the SLC22A1 gene affect blood glucose levels and HbA1c in patients with DM II when they are treated with metformin.(AU)
O diabetes mellitus tipo II (DM II) é uma doenþa que afeta uma grande quantidade de indivíduos. Um medicamento utilizado no tratamento dos doentes é a metformina. Esse medicamento é transportado no interior dos hepatócitos por um transportador codificado pelo gene SLC22A1. Variantes no gene com atividade reduzida podem diminuir a quantidade de Metformina disponível no fígado e reduzir a resposta terapÛutica. Prop¶s-se avaliar diferentes parÔmetros bioquímicos em relaþÒo O dose da metformina e O presenþa de variantes no transportador. Foram estudados 103 pacientes maiores de 18 anos com diagnóstico de DM II tratados com 1700 mg/dia de metformina por mais de 6 meses. Foram analisados 5 polimorfismos no gene SLC22A1; glicemia, HbA1c, funþÒo hepática, perfil lipídico e renal. Os níveis de HbA1c e de glicemia foram superiores em doentes que apresentavam os polimorfismos R61C, G401S, M420del e G465R; embora a diferenþa seja estatisticamente significativa apenas para o HbA1c nos doentes que apresentavam as variantes M420del e G465R (p=0,0273 e 0,0018; respectivamente). A presenþa de polimorfismos com atividade reduzida no gene SLC22A1 afeta os níveis da glicemia e do HbA1c em doentes com DM II quando sÒo tratados com metformina.(AU)
